Derivatives of vitamin



Patented Aug. 22, 1950 DERIVATIVES OF VITAMIN Bs AND PROCESS OFPREPARING SAME Dorothea Heyl, Rahway, Stanton A. Harris, Westfield, andKarl Folkers, Plainfield, N. 5., assignors to Merck & (30., Inc.,Rahway, N. J a corp'p- V,

ration of New Jersey No Drawing. @riginal application July 14, 1944,

Serial No. 545,005. Dividedand this application September 23, 1948,Serial No. 50,882

9 Claims. (c1. 26o 297) This application relates generally to a processfor the preparation of chemical compounds; in a particular sense it isconcerned with the preparation of compounds having physiologicalactivity similar to that of vitamin B6 (2-methyl-3-hydroxy-4,5-bis(hydroxymethyl) pyridine) This application is a divisionof our copending application Serial No. 545,005, filed July 14, 1944,now abandoned.

2 compound (II) can be efiected by the use of common oxidizing agents,for'example, permanganates, chromates and dichromates. The cyclicacetal, 1,3-dihydroxy-1-alkoxy-6- methylfuro-(3,4=-c) -pyridine-7-o1(IV) is obtained preferably byt'reating the reaction product'of nitrousacid and the oxime (III) with a lower aliphatic alcohol such asmethanol, ethanol, and isopropanol. Hydrolysis of the cyclic acetal,

It is known that nutritional factors of uncer- 10 for example withdilute acids, yields an equitain chemical composition, closely relatedin librium mixture of the hemi-acetal and Z-methylphysiological activityto vitamin B6, possess 3 -hydroxy4-formyl-B-hydroxymethylpyridine. Ygreater growth-promoting activity for certain The following exampleillustrates a method of organisms than does vitamin B6 itself. carryingout the present invention, but it is to It is found that the chemicalcompound, be understood that this example is given by way2-methyl-3-hydroxy-4-formyl-5-hydroxymethylof illustration and not oflimitation. pyridine, like the above mentioned nutritional factors, hasseveral hundred fold greater growth Example promoting activity for S,lactis R than does (A) Formation of the oxime (In) vitamin B6.

According to one embodiment of this invention, CHOH it is found that2-methyl-3-hydroxy-4,5-bis(hy- H0 oHioH KMNO droxymethyD-pyridine (I)can be oxidized to 2-methyl-3-hydroxy-4-formyl-5-hydroxymethyl- H30 H01pyridine, (II) and that this last mentioned com- N pound can be isolatedfrom the oxidation reac- CH0 CH=NOH tion mixture by formation of theoxime of this HO onion HO CHQOH compound (III). Further in accordancewith FL this invention, the oxime is reacted with nitrous H3C\ H acidand treated with alcohol to form the cyclic 0 N N acetal (IV), thisacetal'on hydrolysis yields an To about 9.6 g. of2-methyl-3-hydroxy-4,5-diequilibrium mixture of 2-methyl-3hydroxy-4-hydroxymethylpyridine hydrochloride in 200 cc.formyl-5-hydroxymethylpyridine (II), and the of Water, neutralized withabout 3.9 g. of sodium hemi-acetal form of this compound (V). Thesebicarbonate, is added 2 g. of potassium permanreactions may beillustrated as follows: ganate in 150 cc. of water in about one hourwith I\ CHzOH CHO OH=NOH 0 H0 oH2oH HO CHZOH H0 onion Ho, -t1Hi 1 n mIrv HsCLNJ H3CLN/ H3O N/ HaCLN J CHO I H0 OHzOH Ho [II V H C H C 3 N a NAccording to the present invention, it is found that the oxidation ofvitamin B5 (I) to the formyl agitation. The resultant mixture isacidified to about pH 3, concentrated to about cc treated with 20 g. ofsodium acetate and 9.7 g. of hydroxylamine hydrochloride, and cooled.The oxime of 2-methyl-3-hydroxy-4-formyl-5-hydroxy-methyl-pyridine. (M.R. 221-223 (5.) appears as.a precipitate.

(B) Formation of the cyclic acetal (IV) About 0.45 g. of sodium nitritein 2 cc. of. water is added with agitation to 1.12 g. of the oximc in 5cc. of hydrochloric acid (6N) and 13 cc-. of water, and heated to removethe free nitrous acid. The resulting; mixture is. concentrated; under.reduced pressure, and the residue therefrom allowed to stand: with 15..col. of absolute ethanol for about 16 hours, after which, the mixture isfiltered, concentrated, and. crude 1,3-dihydro-Ieethoxy-G-methyl-fiuro-(ZiA-c) -pyridine 7 o1 hydrochloride (M. P.I4l.-lf1-3 C.) is precipitated by'additicn of. etherto the solution.This. crude product is removed and. purified by conventional operations;

In like manner other lower aliphatic; alcohols, such as, methanol orisopropanol, can. be used in place of ethanol. to obtain; acetals having1- methoxyor l-isopropoxy' substituents.

(C) Formation. of. the hemiracetal (V) -aldehyde II equilibrium mixture/OR HC dilHCl About 144 mg. of the cyclic acetal in cc. of I In likemanner acetals having l-methoxy or 1- iso-propoxy substituents can behydrolyzed to obtain the equilibrium mixture of hemi-acetal andaldehyde.

The equilibrium mixture of the hemi-acetal and the aldehyde can bereacted with acids to form corresponding acid salts. For example,reactingv the mixture with sulfuric acid yields the sulfate salt, with ahydrohalide yields the hydrohalide salt.

4 Modifications may be made in carrying out the present inventionwithout departing from the spirit and scope thereof and the invention isto be limited only by the. appended claims.

We claim: l. A compound of the formula:

thereof.

2. A compound of the formula:

wherein R is a lower alkyl group, and hydrohalide salts thereof.

3. A compound of the formula:

QCzHa and acid salts thereof.

4. A compound of the. formula:

l CH2 HCL J a N and hydrohalide salts thereof.

5. The process that comprises reacting 2*-methyl-3-hydroxy-4-oximinomethyl-5 hydroxymethylpyridine with nitrousacid t1 reaction product thus formed with a K37. al1- phatic alcohol,recovering the 1,3dihydro-L alkoxy-G-methyl-furo- (3,4-0) -pyridine--".'o?. thus; formed, hydrolyzing the latter compound and recovering anequilibrium mixture of lfi-dihy dro1 hydroxy-(i-methyl-furo- (3,4 -c)-32 ridine" 7 01 and 2- methyl-3-hydrQXy-4-f0rmyl-5--hydroxymthylpyridine.

6. The process that comprises reacting 2- methyl-3-hydroxy-4-oximinomethyl-5 hydroxymethylpyridine with nitrous acid, treating thereaction product thus formed with a lower aliphatic alcohol andrecovering the 1,3-dihydro-lalkoxy-B-methyl-furo- (3,4-0) -pyridine-7-olthus formed.

'7. The process that comprises reacting 2- methyl-3hydroxy-4-oximinomethyl-5 -hydroxymethylpyridine with nitrous acid,treating the reaction product thus formed with ethyl alcohol andrecovering the 1,3-dihydro-I-ethoxy-6- methyl-furo-(3,4-c)-pyridine-7-ol thus formed.

5 8. The process that comprises hydrolyzing 1,3- dihydro 1alkoxy-fi-methyl-furo-(3,4-0) -pyridine-7-o1 and recovering anequilibrium mixture of 1,3-dihydro-l-hydroxy-S-methyl-furo- (3,4-0)pyridine-7-01 and 2-methy1-3-hydroxy-4-f0rmy1- 5-hydroxymethy1pyridine.

9. The process that comprises hydrolyzing 1,3- dihydro 1ethoxy-fi-methyl-furo- (3,4-0) -pyridine-7-o1 with hydrochloric aicidand recovering 6 an equilibrium mixture of1,3-dihydro-1-hydroxy-G-methyl furo-(3,4-c) -pyridine-'7-o1 and2-methy1-3-hydroXy-4-formy1-5-hydroxymethy1 pyridine.

DOROTHEA HEYL. STANTON A. HARRIS. KARL FOLKERS.

No references cited.

1. A COMPOUND OF THE FORMULA:
 5. THE PROCESS THAT COMPRISES REACTING2MEHTYL-3-HYDROXY-4-OXIMINOMETHYL-5-HYDROXYMETHYLPYRIDINE WITH NITROUSACID TREATING THE REACTION PRODUCT THUS FORMED WITH A LOWER ALIPHATICALCOHOL, RECOVERING THE1,3-DIHYDRO-1ALKOXY-6-METHYL-FURO-(3,4-C)-PYRIDINE-7-OL THUS FORMED,HYDROLYZING THE LATTER COMPOUND AND RECOVERING AN EQUILIBRIUM MIXTURE OF1,3-DIHYDRO-1-HYDROXY-6-METHYL-FURO-(3,4-C)-PYRIDINE7 - OL AND 2 -METHYL-3-HYDROXY-4-FORMYL-5-HYDROXYMETHYLPYRIDINE.